title: Nicotine induces the up-regulation of the α7-nicotinic receptor (α7-nAChR) in human squamous cell lung cancer cells via the Sp1/GATA protein pathway.
abstract: Nicotine, the addictive component of cigarettes, promotes lung cancer proliferation via the α7-nicotinic acetylcholine receptor (α7-nAChR) subtype. The present manuscript explores the effect of nicotine exposure on α7-nAChR levels in squamous cell carcinoma of the lung (SCC-L) in vitro and in vivo. Nicotine (at concentrations present in the plasma of average smokers) increased α7-nAChR levels in human SCC-L cell lines. Nicotine-induced up-regulation of α7-nAChR was confirmed in vivo by chicken chorioallantoic membrane models. We also observed that the levels of α7-nAChR in human SCC-L tumors (isolated from patients who are active smokers) correlated with their smoking history. Nicotine increased the levels of α7-nAChR mRNA and α7-nAChR transcription in human SCC-L cell lines and SCC-L tumors. Nicotine-induced up-regulation of α7-nAChR required GATA4 and GATA6. ChIP assays showed that nicotine induced the binding of GATA4 or GATA6 to Sp1 on the α7-nAChR promoter, thereby inducing its transcription and increasing its levels in human SCC-L. Our data are clinically relevant because SCC-L patients smoked for decades before being diagnosed with cancer. It may be envisaged that continuous exposure to nicotine (in such SCC-L patients) causes up-regulation of α7-nAChRs, which facilitates tumor growth and progression. Our results will also be relevant to many SCC-L patients exposed to nicotine via second-hand smoke, electronic cigarettes, and patches or gums to quit smoking.
authors.affiliation: From the Department of Pharmacology, Physiology, and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia 25755.
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Brown
authors.forename: Haley E
authors.initials: HE
authors.lastname: Perry
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Lau
authors.forename: Dennie V
authors.initials: DV
authors.lastname: Jones
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Pulliam
authors.forename: Brent A
authors.initials: BA
authors.lastname: Thornhill
authors.forename: Clayton M
authors.initials: CM
authors.lastname: Crabtree
authors.forename: Haitao
authors.initials: H
authors.lastname: Luo
authors.forename: Yi Charlie
authors.initials: YC
authors.lastname: Chen
authors.forename: Piyali
authors.initials: P
authors.lastname: Dasgupta
mesh_terms: D045744:Cell Line, Tumor; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D018307:Neoplasms, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D020218:Response Elements; D012907:Smoking / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014028:Tobacco Smoke Pollution; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D009363:Neoplasm Proteins; D018722:Nicotinic Agonists; D016329:Sp1 Transcription Factor; D014028:Tobacco Smoke Pollution; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine
keywords: GATA; Lung Cancer; Nicotinic Acetylcholine Receptors; Proliferation; Sp1